title: Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.
abstract: BACKGROUND
  Typical 2-Cys peroxiredoxin (Prx) is inactivated by overoxidation of the peroxidatic cysteine residue under oxidative stress. However, the significance in the context of vascular disease is unknown.
  
  
  RESULTS
  Immunohistochemical analyses revealed that 2-Cys Prxs, particularly Prx type II, are heavily overoxidized in balloon-injured rodent carotid vessels and in human atherosclerotic lesions. Consistent with this observation, the selective depletion of Prx II exacerbated neointimal hyperplasia in injured carotid vessels. We also found that the epipolythiodioxopiperazine class of fungal metabolites exhibited an enzyme-like activity mimicking 2-Cys Prx peroxidase and manifestly eliminated the intracellular H₂O₂ in the vascular cells. Functionally, the epipolythiodioxopiperazines reciprocally regulated the platelet-derived growth factor receptor-β- and vascular endothelial growth factor receptor-mediated signaling in these vascular cells by replacing Prx II. As a consequence, the epipolythiodioxopiperazines inhibited the proliferative and migratory activities of smooth muscle cells but promoted those of endothelial cells in vitro. Moreover, administration of the epipolythiodioxopiperazines to the injured carotid vessels resulted in a successful recovery by inhibiting neointimal hyperplasia without causing cytotoxicity and simultaneously inducing reendothelialization.
  
  
  CONCLUSIONS
  This study reveals for the first time the involvement of the 2-Cys Prx overoxidation and thus the therapeutic use of their activity mimetic in vascular injuries like stenting.
authors.affiliation: Division of Life and Pharmaceutical Science and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kang
authors.forename: Doo Jae
authors.initials: DJ
authors.lastname: Lee
authors.forename: Jiran
authors.initials: J
authors.lastname: Kim
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: Kihwan
authors.initials: K
authors.lastname: Kwon
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology / Q000627:therapeutic use*; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D010879:Piperazines; D017382:Reactive Oxygen Species; C555444:epipolythiodiketopiperazine; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: coronary restenosis; endothelium; peroxiredoxins; reactive oxygen species; receptor protein-tyrosine kinases